Cooling Compounds

ABSTRACT

A method of providing a cooling sensation to the skin or the mucous membranes of the body by applying thereto a compound of Formula I 
     
       
         
         
             
             
         
       
     
     in which X is H or (CH 2 ) n —R, n is 0 or 1, Y and Z are selected independently from the group consisting of H, OH, phenyl, C1-C4 straight or branched alkyl, or, a C 1 -C 4  straight or branched alkoxy, or X and Y form together a bivalent radical selected from the group consisting of —O—CH 2 —O—, —N═CH—O— and —N═CH—S— which forms together with the carbon atoms to which they are attached a 5-membered ring; and
 
R is a group with non-bonding electrons, R 1  is H or C 1 -C 5  branched alkyl, R2 and R3 are C 1 -C4 branched alkyls, or R 2  and R 3  taken together form a monocyclic, bicyclic or tricyclic radical of up to 10 carbons provided that R 1 , R 2  and R 3  together comprise at least 6 carbons.
 
     The compounds may be incorporated into products such as dentifrices, foodstuffs, confectionery, beverages, and cosmetic and medicinal preparations.

This invention relates to a method for providing a cooling sensation andto compounds that provide this effect.

Cooling compounds, that is, chemical compounds that impart a coolingsensation to the skin or the mucous membranes of the body, are wellknown to the art and are widely used in a variety of products such asfoodstuffs, tobacco products, beverages, dentifrices, mouthwashes andtoiletries.

One class of cooling compounds that has enjoyed substantial success isthat of the N-substituted p-menthane carboxamides. Examples of thesecompounds are described in, for example, British Patent GB 1,421,744.

Although some of the compounds of the prior art have been successfullycommercialized, the intricate structures of the carboxamide moiety makedifficult to produce. These chemicals can only be offered at high price,which limits their use in consumer products.

It has now been found that a category of simple arylcarboxamides offormula I are good cooling compounds and can easily be made fromcommercially available benzoic acids. The invention therefore provides amethod of providing a cooling sensation to the skin or the mucousmembranes of the body by applying thereto a compound of Formula I

in which X is H or (CH₂)_(n)—R, n is 0 or 1, Y and Z are selectedindependently from the group consisting of H, OH, phenyl, C₁-C₄ straightor branched alkyl, or, a C₁-C₄ straight or branched alkoxy, or X and Yform together a bivalent radical selected from the group consisting of—O—CH₂—O—, —N═CH—O— and —N═CH—S— which forms together with the carbonatoms to which they are attached a 5-membered ring, i.e. a 1,3-dioxolanering, a 1,3-oxazole ring or a 1,3-thiazole ring respectively; andR is a group with non-bonding electrons, R¹ is H, CH₃, C₂H₅ or C₃-C₅branched alkyl, R² and R³ are CH₃, C₂H₅ or C₃-C₄ branched alkyl, or twoor more of R¹, R² and R³ taken together form a monocyclic, bicyclic ortricyclic radical of up to 10 carbons provided that R¹, R² and R³together comprise at least 6 carbons.

R¹, R², R³ and the carbon to which they are attached may be, forexample, para-menthyl, bornyl or adamantyl.

R¹, R², R³ may be chiral or racemic.

Particular compounds are those in which R¹ is methyl and R² and R³ areisopropyl, and in which R¹, R² and R³ are all ethyl.

Particular compounds are those in which X is in the 4-position. Otherparticular compounds are those in which X is in the 4-position and Y andZ are H, OH, OMe or methyl or X and Y form together a bivalent radicalselected from the group consisting of —O—CH₂—O—, —N═CH—O— and —N═CH—S—,thus forming together with the carbon atoms to which they are attached a5-membered ring, i.e. a 1,3-dioxolane ring, a 1,3-oxazole ring or a1,3-thiazole ring respectively.

Particular groups R with non-bonding electrons are halogens, OH, OMe,NO₂, CN, Ac, SO₂NH₂, CHO, CO₂H, CONH₂, C1-C4 alkyl carboxylates such asCO₂Et, C1-C4 alkylamides such as CONHMe or heterocycles such as:

Particular R¹, R² and R3 combinations are:

R¹ R² R³ H bornyl H 3-p-menthyl H isopropyl isopropyl methyl isopropylisopropyl ethyl ethyl ethyl

A number of the compounds hereinabove defined are novel. Thus, in afurther embodiment of the present invention, there is provided acompound of the formula I

in which X, Y, Z, R¹, R², R³ are as hereinabove defined, and in whichone of the following provisos applies:(a) R¹ and X are not H, and, R¹, R², R³ and the carbon to which they areattached form an acyclic moiety;(b) R¹ is H, and R², R³ and the carbon to which they are attached forman acyclic moiety, only one of R², R³ being isopropyl or tert-butyl;(c) R¹ is H, R² and R³ are both isopropyl, and X is in the 4-positionand is not H, halogen, Me, MeO, NO₂, aryl, methylenediaryl,N-(4-carbamimidoyl-phenyl)-6-methoxy-pyridine-2-carboxamide,N-(4-carbamimidoyl-phenyl)-benzamide, a heme derivative and R is notmorpholine, N′-phenylpiperazine, phenylmercaptan,p-chlorophenylmercaptan, isoquinoline, an N-linked sulfonamidederivative or an aryl,(d) R¹ is H and R² and R³ are both tert-butyl; X is not H;(e) R¹ is H, R² and R³ together with the carbons to which they areattached form a p-menthane ring and X, Y and Z are not H;(f) R¹ is H, R² and R³ together with the carbons to which they areattached form a p-menthane ring, Z is H and neither X or Y is H or OH;(g) R¹ is H, R² and R³ together with the carbons to which they areattached form a p-menthane ring, Z is H, Y is OH and X is neitherformamide nor NO₂;(h) R¹ is H, R² and R³ together with the carbons to which they areattached form a p-menthane ring, Z and Y are both H, and X is not H,COOH, quinolinylsulfonamide, CF₃, a methylenediaryl or a hemederivative.

Particular examples of such compounds are those corresponding toFormulae II, III and IV, when provisos (a), (b) and (c) apply, and thosecorresponding to Formula V when provisos (e), (f), (g) and (h) apply:

Particular examples of useful stereoisomers are(1R,2S,5R)-5-methyl-2-(1-methylethyl)-cyclohexanamine[(1R,2S,5R)-menthyl] and(2S,5R)-5-methyl-2-(1-methylethyl)-cyclohexanamine [(2S,5R)-menthyl].

The compounds may be easily prepared by amidation of a benzoyl chloridewith an amine or an aminium chloride salt. Amines where R¹═H can be madefrom their corresponding ketone according to Schopohl, M. et al.Synthesis 2003, 17, 2689. Amines where R¹ is C1-C5 alkyl can be preparedfrom their corresponding alcohol according to Jirgensons, A et al.Synthesis 2000, 12, 1709-1712

The invention also provides a method of providing a cooling effect to aproduct that will be orally ingested, applied to the skin or used in atobacco product, comprising the incorporation in the product of aneffective amount of a compound as hereinabove defined. The inventionfurther provides a composition that provides a cooling sensation to theskin or oral cavity, comprising an effective amount of a compound ashereinabove defined. The kinds of compositions in which the compoundshereinabove defined can be used include personal care products such asdentifrices (toothpastes, tooth gels, mouthwashes), cosmetic andmedicinal preparations, such as tablets, lozenges, liquids, creams andsprays, foodstuffs and confectionery, hard candy, beverages, etc.

The “effective amount” required will naturally vary quite widely,depending on the natures of the compound and composition, the type ofapplication and the extent and nature of cooling effect desired. As aresult, any quantities given can only be approximations at best.However, typical concentrations are a maximum of 5000 ppm, that is, 0.5%by weight of the composition. As a general rule, between 50 and 3000 ppmare all that is required for a solid composition. In the case ofbeverages, as low as 15 ppm may be sufficient to generate a desiredcooling effect.

In addition to the cooling compounds, the compositions may contain allthe normal ingredients known to the art that are useful in suchcompositions, in art-recognised quantities.

More than one compound of the type hereinabove described may be used inthe compositions according to this invention. In addition, the compoundsmay be used in conjunction with other known and/orcommercially-available cooling compounds. Such compounds includementhol, menthone, isopulegol, N-ethyl p-menthanecarboxamide (WS-3),N,2,3-trimethyl-2-isopropylbutanamide (WS-23), menthyl lactate, menthoneglycerine acetal (Frescolat® MGA), mono-menthyl succinate (Physcool®),mono-menthyl glutarate, O-menthyl glycerine (CoolAct® 10) and2-sec-butylcyclohexanone (Freskomenthe®).

The incorporation of the compounds into the compositions may be achievedby entirely conventional means.

The invention is now further described with reference to the followingnon-limiting examples.

EXAMPLE 1 Preparation of Menthylamine

41.69 g of hydroxylamine hydrochloride were dissolved in 200 mL ofwater. Under ice cooling, 40 g of NaOH pellets were added. After theNaOH was dissolved, 61.7 g of L-Menthone were added over a period of 10minutes. The mixture was stirred at RT for 70 h. The mixture, containingwhite solid balls, was extracted twice with MTBE. The organic layerswere washed with water and brine, dried over MgSO₄ and concentrated togive 67 g of white solid which is reacted with 12 g of lithium aluminumhydride in 300 mL of MTBE, under ice cooling. The mixture was stirredfor 96 hours at Room Temperature. The light grayish suspension wastreated with acetone and with 40 mL of HCl (1N). The yellowishsupernatant was acidified with HCl (37%) and extracted twice with MTBE.The organic layers were washed with HCl (1N). The combined aqueouslayers were neutralized with NaOH pellets to pH 13 and extracted twicewith MTBE. The organic layers were washed with brine, dried over MgSO₄and concentrated to give 42.3 g of a yellowish liquid which is purifiedby distillation.

EXAMPLE 2 Preparation of 1-methyl-1-isopropylisobutylaminium chloride

18.1 g of 1-methyl-1-isopropylisobutanol and 15.74 g ofChloroacetonitrile are dissolved in 27.2 mL of acetic acid and themixture was cooled in an ice bath. 27.3 g of sulfuric acid was addedover a period of 20 minutes. The mixture was stirred at 0° C. for 1 hand for another 4 h at room temperature. The mixture was quenched withice and extracted with MTBE. The organic layers were washed twice withNaHCO3, brine, dried over MgSO₄ and concentrated to recover 32.3 g of ayellow oil containing N-1-methyl-1-isopropylisobutyl 1-chloroacetamidewith the following properties:

1HNMR (300 MHz, CDCl3) δ in ppm (two rotomers): 6.4 and 6.05 (broad s.,1H), 3.92 and 3.97 (d, 2H), 2.09 and 1.93 (m, 2H), 1.37 and 1.32 (d,3H), 0.93 and 0.84 (m, 12H) 13CNMR (75 MHz, CDCl3) δ in ppm (tworotomers): 165, 164.5, 63.1, 58.2, 45.25, 43.4, 43.1, 34.35, 26.95,26.9, 24.6, 24.2, 17.7, 17.5, 14.7, 16.6, 8.35

MS/EI: 207 (M^(+·)), 205 (M^(+·)), 192, 190, 164, 162, 150, 148, 136,134, 97

This oil was mixed with 13.7 g of thiourea and 50 mL of acetic acid in250 mL of ethanol. The mixture was heated at reflux overnight. 500 mL ofwater was added and the suspension was stirred at room temperature for30 minutes. NaOH pellets are added to set the solution to alkaline pH.The yellowish solution was extracted three times with pentane and theorganic layers were washed with brine and dried over MgSO₄. 1 L of HClin Et2O (1M) was added and the mixture was stirred at room temperaturefor 1 h. The mixture was concentrated to obtain 5.3 g of white crystalswith the following physical properties:

1HNMR (300 MHz, CD3OD) δ in ppm (two rotomers): 2.12 and 2.02(heptuplet, 2H), 1.37 and 1.31 (s, 3H), 1.03 (ddd, 6H), 0.92 (dd, 6H)

13CNMR (75 MHz, CD3OD) 6 in ppm (two rotomers): 63.3, 59.3, 47.2, 33.8,27.75, 24.5, 24.3, 24.2, 17.7, 17.4, 17.1, 16.9, 8.5

MS/EI: 263 (M^(+·)), 248, 220, 192, 152, 135, 107, 92

EXAMPLE 3 Preparation of 1,1-dimethylpropylamine

16 g of 1,1-diethylpropanol was treated in a way similar to that ofexample 2 to give the desired product with the following physicalproperties:

1HNMR (300 MHz, CDCl3) δ in ppm: 1.33 (qd, 6H), 0.82 (td, 9H)

13CNMR (75 MHz, CDCl3) δ in ppm: 53.2, 31.4, 7.6

MS/EI: 114 (M−1⁺), 98, 86, 69, 56

EXAMPLE 4 Preparation of N-1-methyl-1-isopropylisobutyl anisamide

0.10 g of 1-methyl-1-isopropylisobutylaminium chloride from example 2and 0.20 g of pyridine were dissolved in 5 mL of MTBE and 0.16 g ofp-anisoyl chloride were added. The mixture was stirred at roomtemperature overnight.

The resulting suspension was partitioned between MTBE and NaHCO₃ andextracted with MTBE. The organic layers were washed with brine, driedover MgSO₄ and concentrated to obtained 0.38 g of crude product, whichwas purified by recrystallization in hexane.

1HNMR (300 MHz, CDCl3) δ in ppm (two rotomers): 8.1 and 7.68 (d, 2H),6.99 and 6.90 (d, 2H), 5.88 (broad s., 1H), 3.83 and 3.9 (s, 3H), 2.19and 2.04 (heptuplet, 2H), 1.44 and 1.2 (s, 3H), 0.99 (dd, 6H), 0.86 (dd,6H)

13CNMR (75 MHz, CDCl3) δ in ppm (two rotomers): 166, 163, 133, 128.5,128, 114.5, 113.5, 57.9, 55.3, 49.7, 44.8, 27.0, 26.9, 25.5, 24.7, 24.4,17.9, 8.5

EXAMPLE 5

Following the same procedure according to Example 4 the compounds listedin Table 1 were synthesised.

TABLE 1 No Structure Name Physical Data A

N-(1-methyl-1-isopropylbutyl)-benzamide MS: 233, 218, 190,122, 105, 77 B

N-(1-methyl-1-isopropylbutyl)-4-Cyano-benzamide MS: 258, 243, 215,173,130, 102 C

N-(1-methyl-1-isopropyl-isobutyl) O-methylterephthalamate MS: 291, 276,248,163, 135 D

N-(3-p-menthyl) O-methylterephthalamate MS: 317, 302, 274,232, 180, 163,135 E

N-(1,1-diethylpropyl)biphenyl-4-carboxamide MS: 295, 266, 224,198, 181,152 F

N-(1-methyl-1-isopropyl-isobutyl) biphenyl-4-carboxamide MS: 309, 294,266,198, 181, 152 G

N-(1-isopropylbutyl) 3-cyanobenzamide MS: 244, 229, 201,130, 102 H

N-(1-isopropyl-isobutyl)benzo[1,3]dioxole-5-carboxamide MS: 263, 248,220,165, 149, 121 K

N-(1-methyl-1-isopropyl-isobutyl)benzo[1,3]dioxole-5-carboxamide MS:277, 262, 234,166, 149, 121 L

N-(1,1-diethylpropyl)benzo[1,3]dioxole-5-carboxamide MS: 263, 234,165,149, 121 M

N-bornyl benzamide MS

EXAMPLE 6 Cooling Effect

The cooling intensity of the compounds was determined by a trained panelof 4 to 8 people according to the isointensity method as describedbelow.

Aqueous solutions of various concentrations of a chemical compound wereprepared and tasted. The cooling intensity of each solution was comparedto that of an aqueous solution of the reference compound at 2 ppm,namely menthol. The results are given in the list below.

rel. cooling Example Chemical name intensity Ex. 4N-1-methyl-1-isopropylisobutyl 1.1 anisamide Ex. 5AN-(1-methyl-1-isopropylbutyl) 0.1 benzamide Ex. 5BN-(1-methyl-1-isopropylbutyl) 1.0 4-cyanobenzamide Ex. 5CN-(1-methyl-1-isopropyl-isobutyl) 1.7 O-methyl terephthalamate Ex. 5DN-(3-p-menthyl) O-methyl 2.5 terephthalamate Ex. 5EN-(1,1-diethylpropyl) biphenyl- 1.2 4-carboxamide Ex. 5FN-(1-methyl-1-isopropyl-isobutyl) 1.5 biphenyl-4-carboxamide Ex. 5GN-(1-isopropylisobutyl) 0.2 3-cyanobenzamide Ex. 5HN-(1-isopropyl-isobutyl) 0.9 benzo[1,3]dioxole-5-carboxamide Ex. 5KN-(1-methyl-1-isopropyl-isobutyl) 0.9 benzo[1,3]dioxole-5-carboxamideEx. 5L N-(1,1-diethylpropyl) 0.3 benzo[1,3]dioxole-5-carboxamide Ex. 5MN-bornyl benzamide 0.6

EXAMPLE 7

Application in mouthwash Alcohol 95% 177 mL Sorbitol 70% 250 g Compoundof example 4 as 50 mL a 1% solution in alcohol Peppermint oil,Terpeneless 0.300 g Methyl salicylate 0.640 g Eucalyptol 0.922 g Thymol0.639 g Benzoic acid 1.500 g Pluronic F127 5.000 g Sodium Saccharin0.600 g Sodium Citrate 0.300 g Citric Acid 0.100 g Water q.s. 1 liter

All the ingredients were mixed. 30 mL of obtained solution was put inthe mouth, swished around, gargled and spit out. A pleasant coolingsensation was felt in every area of the mouth.

EXAMPLE 8

Application in toothpaste Opaque toothgel 97.000 g  Compound of example5B 2.500 g as a 2% solution in PG Peppermint oil, Terpeneless 0.500 g

The ingredients were mixed in the toothgel, a piece of toothgel was puton a toothbrush and a panelist's teeth were brushed. The mouth wasrinsed with water and the water spit out. A longlasting coolingsensation was felt by the panelist in all areas of the mouth.

1. A method of providing a cooling sensation to the skin or the mucousmembranes of the body by applying thereto a compound of Formula I

in which X is H or (CH₂)_(n)—R, n is 0 or 1, Y and Z are selectedindependently from the group consisting of H, OH, phenyl, C1-C4 straightor branched alkyl, and C₁-C₄ straight or branched alkoxy, or X and Yform together a bivalent radical selected from the group consisting of—O—CH₂—O—, —N═CH—O— and —N═CH—S— which forms together with the carbonatoms to which they are attached a 5-membered ring; and R is a groupwith non-bonding electrons, R¹ is H or C₁-C₅ branched alkyl, R2 and R3are C₁-C4 branched alkyls, or R² and R³ taken together form amonocyclic, bicyclic or tricyclic radical of up to 10 carbons providedthat R¹, R² and R³ together comprise at least 6 carbons.
 2. A methodaccording to claim 1, in which R is selected from the group consistingof OH, OMe, NO₂, CN, Ac, SO₂NH₂, CHO, CO₂H, CONH₂, C₁-C₄ alkylcarboxylates, C₁-C₄ alkylamides and heterocycles.
 3. A method accordingto claim 2, in which the heterocycle is selected from the groupconsisting of.


4. A method according to claim 1, in which R¹ is methyl and R² and R³are isopropyl, or in which R¹, R² and R³ are all ethyl.
 5. A methodaccording to claim 1 in which R¹, R² and R³ are selected according tothe following table: R¹ R² R³ H bornyl H 3-p-menthyl H isopropylisopropyl methyl isopropyl isopropyl ethyl ethyl ethyl


6. A method according to claim 1, in which X is in the 4-position.
 7. Amethod according to claim 6, in which Y and Z are independently selectedfrom H, OH, OMe and methyl.
 8. A method according to claim 1, in whichthe cooling effect is provided in a product that is to be orallyingested, applied to the skin or used in a tobacco product.
 9. Acomposition that provides a cooling sensation to the skin or oralcavity, comprising an effective amount of a compound of Formula I

in which X is H or (CH₂)_(n)—R, n is 0 or 1, Y and Z are selectedindependently from the group consisting of H, OH, phenyl, C1-C4 straightor branched alkyl, and C₁-C₄ straight or branched alkoxy, or X and Yform together a bivalent radical selected from the group consisting of—O—CH₂—O—, —N═CH—O— and —N═CH—S— which forms together with the carbonatoms to which they are attached a 5-membered ring; and R is a groupwith non-bonding electrons, R¹ is H or C₁-C₅ branched alkyl, R2 and R3are C₁-C4 branched alkyls, or R² and R³ taken together form amonocyclic, bicyclic or tricyclic radical of up to 10 carbons providedthat R¹, R² and R³ together comprise at least 6 carbons.
 10. A compoundof the formula I

in which X is H or (CH₂)_(n)—R, n is 0 or 1, Y and Z are selectedindependently from the group consisting of H, OH, phenyl, C1-C4 straightor branched alkyl, and C₁-C₄ straight or branched alkoxy, or X and Yform together a bivalent radical selected from the group consisting of—O—CH₂—O—, —N═CH—O— and —N═CH—S— which forms together with the carbonatoms to which they are attached a 5-membered ring; and R is a groupwith non-bonding electrons, R¹ is H or C₁-C₅ branched alkyl, R2 and R3are C₁-C4 branched alkyls, or R² and R³ taken together form amonocyclic, bicyclic or tricyclic radical of up to 10 carbons providedthat R¹, R² and R³ together comprise at least 6 carbons, and in whichone of the following provisos applies: (a) R¹ and X are not H, and, R¹,R², R³ and the carbon to which they are attached form an acyclic moiety;(b) R¹ is H, and R², R³ and the carbon to which they are attached forman acyclic moiety, only one of R², R³ being isopropyl or tert-butyl; (c)R¹ is H, R² and R³ are both isopropyl, and X is in the 4-position and isnot H, halogen, Me, MeO, NO₂, aryl, methylenediaryl,N-(4-carbamimidoyl-phenyl)-6-methoxy-pyridine-2-carboxamide,N-(4-carbamimidoyl-phenyl)-benzamide, a heme derivative and R is notmorpholine, N′-phenylpiperazine, phenylmercaptan,p-chlorophenylmercaptan, isoquinoline, an N-linked sulfonamidederivative or an aryl, (d) R¹ is H and R² and R³ are both tert-butyl; Xis not H; (e) R¹ is H, R² and R³ together with the carbons to which theyare attached form a p-menthane ring and X, Y and Z are not H; (f) R¹ isH, R² and R³ together with the carbons to which they are attached form ap-menthane ring, Z is H and neither X or Y is H or OH; g) R¹ is H, R²and R³ together with the carbons to which they are attached form ap-menthane ring, Z is H, Y is OH and X is neither formamide nor NO₂; (h)R¹ is H, R² and R³ together with the carbons to which they are attachedform a p-menthane ring, Z and Y are both H, and X is not H, COOH,quinolinylsulfonamide, CF₃, a methylenediaryl or a heme derivative. 11.A compound according to claim 10, in which the compound corresponds toone of Formulae II, III and IV, when provisos (a), (b) and (c) apply,and to Formula V when provisos (e), (f), (g) and (h) apply: